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All-trans retinoic acid therapy of acute promyelocytic leukemia represents the most successful example of differentiation-induction therapy in clinical oncology. However, acute promyelocytic leukemia represents only a small minority (10–15%) of the myeloid leukemias. Recent studies provide significant insight into why some myeloid leukemias respond dramatically to all-trans retinoic acid mediated differentiation therapy, whereas others do not.Utilizing in-vitro experimental models of all-trans retinoic acid triggered myeloid leukemia differentiation, specific genes that are important regulators of granulocytic differentiation have been identified including transcription factors, apoptosis regulators, protein synthesis inhibitors and protein degradation factors. Moreover, recent studies have identified repressive chromatin marks generated by the aberrant, acute promyelocytic leukemia specific promyelocytic locus gene–retinoic acid receptor α (PML–RARα) fusion protein as well as the specific enzymes that mediate these chromatin changes.The molecular basis for PML–RARα- mediated leukemogenesis is complex involving both the repression of numerous potential target genes and critical ‘off promoter’ functional activity of this fusion protein. The acute promyelocytic leukemia specific repressive chromatin marks related to PML–RARα activity may be present in other myeloid leukemias as well. This suggests alternative approaches for treating myeloid leukemia involving therapeutic agents that inhibit heterochromatin formation and enhance transcriptional activity. All-trans retinoic acid or related compounds may also play a significant role in enhancing hematopoietic stem cell self-renewal as well as the production and differentiation of regulatory T cells.